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Programmed cell death is essential for maintaining cellular homeostasis, and emerging forms such as necroptosis, pyroptosis, and ferroptosis (NPF) are associated with cancer progression. However, their exact roles remain poorly characterised. In this study, we investigated the role of NPF-related genes in cancer prognosis by analysing gene expression and clinical data from the TCGA pan-cancer dataset. A multigene prognostic model was developed to predict patient survival. Pathway enrichment and tumour microenvironment analyses revealed significant associations between NPF-related genes and immune cell types, particularly highlighting the link between TLR4 expression and macrophage infiltration. Elevated TLR4 expression in tumour cells was correlated with an immunosuppressive environment, positioning TLR4 as a potential therapeutic target. Moreover, treatment with the TLR4 inhibitor TAK-242 was shown to inhibit cell proliferation and migration in PANC-1 and SW1990 cell lines. These findings underscore the potential of NPF-related pathways as prognostic biomarkers and support TAK-242 as a promising therapeutic candidate for cancer treatment.